Abstract In a phenotype-driven, genetic screen to identify novel genes that affect -cell function, we found a mutation in Sec61a1 in a family of mice with diabetes. Sec61a1 encodes the protein conducting subunit of the endoplasmic reticulum (ER) translocation channel, which is responsible for protein import into the ER. Diabetes in Sec61a1 mutant mice is correlated with -cell apoptosis and massively distended ER. The distended ER is consistent with ER stress, an accumulation of unfolded proteins within the ER. The cell mounts a response to ER stress, the unfolded protein response, which includes up regulation of protein folding chaperones (e.g. Bip), and, in the case that ER stress cannot be relieved, up regulation of the proapoptotic transcription factor Chop. Bip and Chop are both up regulated in diabetic Sec61a1 mutant animals. Thus, our hypothesis is that Sec61a1 mutation leads to ER stress, -cell apoptosis, and diabetes. The experiments in this proposal are designed to test this hypothesis, to understand the mechanism by which Sec61a1 mutation leads to ER stress, and to ask if ER stress plays a role in the -cell dysfunction that is part of type 2 diabetes.